Adjuvant hepatic arterial infusion pump chemotherapy after resection of colorectal liver metastases in patients with a low clinical risk score - a randomized controlled trial

Colorectal liver metastases
Colorectal cancer (CRC) is the third most common cancer with an annual
incidence of 14,000 patients in the Netherlands. More than half of these
patients will eventually develop colorectal liver metastases (CLM), of whom 25%
have resectable disease at first presentation.(1)

The efficacy of resection of CLM has never been evaluated in a randomized
controlled trial (RCT). However, 10-year overall survival (OS) of 20% to 30%
has been reported after resection of CLM, which is equivalent to cure.(2) As
compared to resection, systemic chemotherapy alone rarely results in 10-year
OS. Complete resection of CLM (with or without ablation), if feasible, is
therefore the standard of care. Most patients (up to 80%) develop recurrent
disease after curative intent resection of CLM, which in about 50% of patients
is confined to the liver.(2) A large phase 3 trial investigating perioperative
systemic chemotherapy for patients with resectable CLM found overlapping
survival curves after a median follow-up of 8.5 years: 5-year OS was 51% with
perioperative chemotherapy versus 48% with surgery alone (p=0.34).(3, 4) This
was an unexpected outcome, because systemic chemotherapy is effective in the
adjuvant setting for stage III colorectal cancer and in the palliative setting
for unresectable stage IV disease. Consequently, better adjuvant treatment is
needed.

The risk of recurrence is commonly determined by using the Clinical Risk Score
(CRS).(5) The CRS is the sum of five poor prognostic factors: node-positive
CRC, disease free interval below 12 months, more than one CLM, largest tumor
above 5cm, and serum CEA level above 200 µg/L. More than half of patients with
CLM have a low CRS of 0 to 2. The risk of recurrence in these patients is still
70%. No RCT are currently available that demonstrate an improvement of adjuvant
chemotherapy certain subgroups of patients. The CRS might be helpful to select
patients that benefit from adjuvant chemotherapy after surgical treatment of
CLM.

Hepatic arterial infusion pump chemotherapy - Mechanism of action
Hepatic arterial infusion pump (HAIP) chemotherapy for liver tumors is a
treatment that has been developed at Memorial Sloan Kettering Cancer Center
(MSKCC, New York, USA). It is currently not available in the European Union,
because floxuridine is not registered in the EU. The biological rationale for
intra-arterial chemotherapy is that the hepatic artery rather than the portal
vein is responsible for most of the blood supply to liver tumors.(6, 7)
Moreover, up to 95% of drugs such as floxuridine (FUDR) is extracted by the
liver during the first-pass, allowing an up to 400-fold increase in hepatic
exposure with minimal systemic exposure.(8, 9) Intra-arterial chemotherapy is
delivered in the hepatic artery via a surgically implantable pump with a
catheter in the gastroduodenal artery. The pump is filled percutaneously and
the liver is continuously perfused with chemotherapy for two weeks, which is
repeated after a two-week rest period.

Evidence for adjuvant HAIP chemotherapy
Four randomized controlled trials (RCT) have evaluated adjuvant HAI
chemotherapy.(10-14) In the first RCT at Memorial Sloan Kettering Cancer Center
(MSKCC), patients received adjuvant systemic 5-fluorouracil (5-FU) and HAIP
chemotherapy or systemic 5-FU alone. The primary outcome of 2-year survival was
85% with HAIP versus 69% (p=0.02).(10) After a median follow-up of 8.5 years,
the median OS was 68 months with HAIP versus 59 months (p=0.10).(10, 13) Median
PFS was 31 months with HAIP versus 17 months (p=0.02). Hepatic PFS at 2-years
was 85% with HAIP versus 50% (p=0.001).

The second RCT was a multi-site study that found a 4-year recurrence rate of
25% in patients treated with adjuvant HAIP chemotherapy versus 46% without HAIP
chemotherapy (p=0.04).(11) A third multi-site RCT used intra-arterial 5-FU
instead of floxuridine.(12) The study was closed prematurely when no difference
was found at interim analysis. 5-FU has a much smaller first pass effect,
resulting in lower tumor exposure and more systemic toxicity. Moreover, an
external (rather than implanted) pump was used and many patients had pump
failure; 26% never received HAIP chemotherapy in the intervention arm.

Studies from France used intra-arterial oxaliplatin with a percutaneously
placed catheter connected to a mediport.(15) This approach has not been
evaluated in an RCT. The disadvantage is the much lower first pass effect in
the liver of oxaliplatin resulting in lower concentration in the liver tumors
and higher systemic exposure and toxicity. Moreover, the mediport doesn*t allow
for continuous long-term perfusion.

The NCCN guideline recommends adjuvant HAIP chemotherapy for CLM as an option
in experienced centers (Category 2B). Adjuvant HAIP chemotherapy for CLM has
not been widely adopted outside MSKCC.(16) Another phase 3 RCT is required to
compare adjuvant HAIP chemotherapy for CLM with surgery alone.

A recent retrospective analysis evaluated 2368 consecutive patients undergoing
complete resection of CLM with and without adjuvant HAIP chemotherapy at MSKCC
between 1992 and 2012.(17) The median OS with HAIP chemotherapy was 67 months
versus 44 months without HAIP chemotherapy (p<0.001). After adjusting in
multivariable analysis for seven independent prognostic factors including
adjuvant modern systemic chemotherapy, the hazard ratio (HR) of HAIP
chemotherapy was 0.70 (95% CI: 0.60-0.80, p<0.001).(17) The median OS in the
group without HAIP chemotherapy was similar to the 45 months found in a series
of 2715 patients from the UK where no HAIP chemotherapy was used.(18) Subgroup
analyses of patients with a low CRS (0-2 points) found a median OS with HAIP
chemotherapy of 89 months versus 53 months without HAIP chemotherapy (p<0.001).
(19)

Safety
HAIP chemotherapy is a complex treatment with a large involved
multidisciplinary team. Both subcutaneous placement of the pump and the
administration of HAIP chemotherapy itself are complex procedures. Adverse
events have been well characterized in the setting of MSKCC.(20)

Imaging to assess adequate perfusion of pump
Prior to the first administration of intra-arterial chemotherapy, bilobar
hepatic perfusion and lack of extrahepatic perfusion are confirmed by
post-operative technetium-99-labeled macroaggregated albumin (MAA) nuclear
medicine scanning. MAA is administered through the IP2000V bolus port. Within 1
hour after MAA injection, a SPECT/CT scan is performed. The total radiation
dose of the Tch99 MAA scan is approximately 3-4 mSv. This has been the default
method of imaging in MSKCC.

Concerns with MAA administration are the difficulties in logistics, the low
resolution of SPECT imaging, the absences of anatomical information of vascular
structures and the possible mismatch between MAA deposition in the liver and
distribution of floxuridine during treatment.

Alternatively, CT with contrast injection through the bolus port of an
indwelling hepatic catheter provides high resolution information on the anatomy
of the post-operative vascular status of the hepatic artery and braches, and
the uptake of contrast agent in the liver parenchyma and possible new liver
metastases (a pre-treatment CT can therefore be omitted).(21) Using this
technique, the distribution of contrast agent is depicted during a specific
phase, i.e. a single point in time, without providing information on the
dynamic distribution of contrast agent in the liver parenchyma. Previous
experience of hepatic perfusion imaging using dual source CT is solely based on
the intravenous administration of contrast agents with high flow rates of 4 to
8 ml per second. In this study, contrast agent is administered through the
dedicated bolus port of the IP2000V pump while acquiring images using dual
source perfusion CT at a temporal resolution of 1.5 second. Because of

This study has been transitioned to CTIS with ID 2024-512850-10-00 check the CTIS register for the current data.

The primary objective is to compare the efficacy of surgery and adjuvant HAIP
chemotherapy to surgery alone in patients with resectable colorectal liver
metastases with a low clinical risk score (CRS 0-2 point). Secondary objectives
are to compare postoperative complications, adverse events, quality of life,
and costs between the two arms. Another secondary objective is to determine
whether CT angiography can replace a nuclear medicine scan to rule out
extrahepatic perfusion of the pump. Next, we aim to identify predictive
biomarkers for the efficacy of HAIP chemotherapy and study the pharmacokinetic
profile of floxuridine.

A randomized controlled open label, multi-site comparative trial

Resection of CLM, pump placement and adjuvant HAIP chemotherapy.

Patients in arm A receive the current standard of care, which is resection of
the CLM. Burden and risk are the same as with the standard of care, except for
filling out quality of life (QoL) questionnaires and additional blood samples
(3 time points). All patients are asked to fill out quality of life
questionnaires at baseline and 3, 6, 9, 12, 24, and 60 months after surgery.
Patients randomized to arm B have a HAI pump surgically implanted placed at the
time of resection of CLM. The study intervention comes in addition to the
standard of care. Prior to the first administration of HAIP chemotherapy a
technetium-99-labeled macroaggregated albumin nuclear medicine scan and a CT
angiography are performed to confirm bilobar hepatic perfusion and rule out
extrahepatic perfusion. Patients will proceed with 6 cycles of chemotherapy.
Follow-up after treatment is identical to the standard of care. Surgical
complications related to HAIP pump placement are uncommon (<10%), but include
hepatic artery thrombosis, pump pocket infection, pump dysfunction, pump
dislocation, and arterial haemorrhage at the site of arterial catheter
insertion. The radiation dose of the Tch99 MAA scan is 3-4 mSv. The radiation
dose of the CT angiography is 15 mSv, which is comparable to a diagnostic CT of
the abdomen. A total of 5-10 ml contrast agent will be infused which with a
negligible effect on renal function. HAIP chemotherapy will require two
hospital visits for each cycle, with a maximum total of 12 visits. HAIP
chemotherapy toxicities include ulcer disease and biliary sclerosis, which can
both be largely avoided by imaging prior to treatment and monitoring of liver
tests and dosages adjustments, if needed. Systemic side effects with HAIP
chemotherapy of floxuridine are rare (<1%). The amount of blood samples that
will be taken is for the biomarker study is 20 ml per time point. The number of
time points is 3 for patients randomized to arm A (total volume 60 ml), and 5
for patients randomized to arm B (total volume 100 ml). The pharmacokinetic
profile of floxuridine will be determined by blood samples drawn during 10 time
points in this study in patients randomize do arm B. The amount of blood is 4.5
ml per time point, with a total of 50 ml. The burden and risks associated with
taking the amount and number of blood(samples) in this study are negligible.
The expected benefit in median OS found in propensity score analysis of more
than 2000 patients was 36 months in patients with al low CRS (89 with versus 53
months without HAIP chemotherapy).